THE INTERNET STROKE CENTER

PRESENTATIONS AND DISCUSSIONS ON STROKE MANAGEMENT

Anticoagulation in Acute Ischemic Stroke

William J. Powers, M.D. Departments of Neurology and Radiology Washington University School of Medicine Stroke Center at Barnes-Jewish Hospital

TABLE OF CONTENTS
An Introduction to Heparin Clinical Trials of Anticoagulation in Stroke Additional Studies Additional Studies and Conclusions References 2 4 6 8 10

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An Introduction to Heparin
What is Heparin? Heterogeneous collection of straight chain anionic sulfated mucopolysaccharides usually obtained from animal lung or intestine Potentiates activity of antithrombin III - an endogenous inhibitor of coagulation factors IIa, IXa and Xa Binds to platelets and plasma proteins Heparinoids and Low Molecular Weight Heparinseparin Pharmacological Reduced anti-IIa eect, primary eect on Xa Reduced platelet interaction Reduced plasma protein binding Clinical Assay activity as anti-Xa units Longer half-life Reduced bleeding Intravenous Heparin for Partial Stable Stroke 225 patients with acute ischemic stroke and partial motor de cits Onset within 48 hours Exclusions: Progression within 1 hour Diastolic BP > 110 Cardiac source

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Progression at 7 days Heparin - 19/112 (17%) Placebo - 22/113 (19.5%) p=.62 - 95% CI -8.7 to +13.7% No dierence in number improved, overall functional status or death Late Results

Three months No dierence in functional activity level One year Higher mortality in heparin group (p<.01) No dierence in functional activity level Source: Ann Internal Med 1986: 105:825-828

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Clinical Trials of Anticoagulation in Stroke

Recently Published Clinical Trials International Stroke Trial (IST) Lancet 1997; 349: 1569-1581 Hong Kong Nadroparin Trial (HK) New England Journal of Medicine 1995; 333:1588-1593 Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Journal of the American Medical Association 1998; 279: 1588-1593

Trial Format IST Entry Endpoint Duration Drug Class Dose Time 5000 SC BID 12,500 SC BID 14 days <48 hrs Dead/Dependent 6 months Heparin HK <48 hrs Dead/Dependent 6 months Nadroparin LMWH 4100 SC QD 4100 SC BID 10 days TOAST <24 hrs Good 3 months ORG 10172 Heparinoid 7200 IV/day 7 days

Recurrent Ischemic Stroke IST Time HD LD Control 14 days 3.2% 2.6% 3.8% HK 10 days 2% 1% 1% 1.1% TOAST 7 days 1.1%

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Percent with Poor Outcome IST HD LD Control Results Intracranial Hemorrhage IST Time HD LD Control 14 days 1.8% 0.7% 0.4%* *p<.05 Major Extracranial Hemorrhage IST Time HD LD Control 14 days 2% 0.6% 0.4%* HK 10 days 0% 0% 1% 1.6% TOAST 10 days 5% HK 10 days 0% TOAST 10 days 2.2% 62.6% 63.1% 62.9% Negative HK 45% 52% 65% p=.007 26.3* Negative TOAST 24.8%*

2%
1.0% 0.6%

*p<.05 HK data for major GI hemorrhages only

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Additional Studies
Fraxiparine in Ischemic Stroke Study Death / Dependency at Six Months Placebo Number Death Barthel <85 Combined 250 68 74 56.8% LD 272 73 82 57.2% HD 245 73 75 59.2%

Fraxiparine is the proprietary name for nadroparin Source: New England Journal of Medicine 1995 Dec 14;333(24):1588-1593

Heparin Complications in Patients with Cerebrovascular Disease Symptomatic CNS hemorrhage in 1-4% Serious non-CNS hemorrhage in 2-3% Sources: Rothrock & Hart: Annals of Internal Medicine 1991; 115:885-895 Camerlingo et al: Archives of Neurology 1994; 51:462-467 Anticoagulant Treatment in Progressing Stroke Unblinded, randomized trial of heparin (125 mg IV x1, IM q6H x 2) then phenindione PT 2-3x control for 3 weeks. Number recovered or improved at 6 months: Control 19/38 Anticoagulation 26/38 (p=.16) Source: British Medical Journal 1961 2:70-73 Anticoagulant Therapy in Thrombosis in Evolution Unblinded, randomized trial of heparin (50 mg IV q4h if < 1week until dicumarol therapeutic) then dicumarol for PT 15-25%. Progression of de cit: 1 month - control 10/67 vs Rx 8/61 6 months - control 13/67 vs Rx 8/61

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 12 months - control 18/67 vs Rx 9/61 Source: Fisher, Neurology 1961 11:119-131, Baker et al, Neurology 1962 12:823-835 Heparin Treatment of Progressing Stroke-I Prospective study of 36 patients who worsened after admission and were then treated with heparin for 7 hours to 21 days. Further progression: Carotid 13/19 Vertebrobasilar 2/8 Lacunar 2/9 Source: Haley et al: Stroke 1988; 19:10-14 Heparin Treatment of Progressing Stroke-II Retrospective chart review of 69 patients: 27 (39%) continued to deteriorate 2 due to CNS hemorrhage 12 (17%) stabilized 30 (44%) improved 10 (14%) developed hemorrhagic side eects Source: Slivka & Levy, Stroke 1990; 21:1657-1662

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Additional Studies and Conclusions

Cerebral Embolism Study Group Un-blinded, prospective randomized study of clinically diagnosed cardio-embolic stroke within 48 hours treated with heparin for 48 hours then warfarin. Results at 14 days: Stroke - control 2/21 vs Rx 0/24 Death - control 2/21 vs Rx 0/24 Source: Stroke 1983; 14:668-670-1662

International Stroke Trial Atrial Fibrillation Heparin Number randomized Recurrent Ischemic Stroke Hemorrhagic Stroke Total New Stroke Data for first 14 days Source: Lancet 1997; 349:1569-1581 1557 2.8% 2.1% 4.9% Control 1612 4.9% 0.4% 5.3%

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Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Cardioembolism ORG 1072 Number randomized Recurrent Stroke Data for first 7 days Source: Journal of the American Medical Association 1998; 279: 1588-1593 Retrospective Stroke Subtype Analysis Five subtypes analyzed for two dierent endpoints in addition to 4 analyses for total group = 14 analyses p < .05/14 = p< .0036 Large artery atherosclerosis Favorable outcome p=.04 Very favorable outcome p=.02 No signi cant dierence 143 0% Control 129 1.6%

Cardiac Embolism Conclusions IST showed no bene t for the subgroup with atrial brillation TOAST showed no bene t for the subgroup with cardioembolism

Summary Patients with lower extremity paralysis should receive DVT prophylaxis with low dose anticoagulation. Anticoagulation with heparin or heparin like drugs has no bene cial eect on: Progression or early recurrence Long term functional status Any subgroup of patients

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References
International Stroke Trial (IST) Lancet 1997; 349: 1569-1581 Hong Kong Nadroparin Trial: "Low-molecular-weight heparin for the treatment of acute ischemic stroke" New England Journal of Medicine 1995; 333:1588-1593 Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Journal of the American medical Association 1998; 279: 1265-1272 Rothrock & Hart "Antithrombotic therapy in cerebrovascular disease." Annals of Internal Medicine 1991; 115:885-895 Camerlingo et al. "Immediate anticoagulation with heparin for rst-ever ischemic stroke in the carotid artery territories observed within 5 hours of onset." Archives of Neurology 1994; 51:462-467 Haley et al. "Failure of heparin to prevent progression in progressing ischemic infarction." Stroke 1988; 19:10-14 Duke RJ, Bloch RF, Turpie AG, Trebilcock R, Bayer N: "Intravenous heparin for the prevention of stroke progression in acute partial stable stroke." Annals of Internal Medicine 1986; 105:825-828 Slivka & Levy: "Natural history of progressive ischemic stroke in a population treated with heparin." Stroke 1990; 21:1657-1662 Stroke 1983; 14:668-670-1662 Baker et al: Neurology 1962 12:823-835 Carter: Brit Med J 1961 2:70-73 Fisher: Neurology 1961 11:119-131

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